Synucleins are a family of small proteins, about 14 kDa that are expressed at high levels in nervous tissues. The three members of the family are α-, β-, and γ-synucleins.
α-Synuclein is expressed mainly in brain tissues and is primarily located at the presynpatic terminal of neurons. The primary structure of the human form of α-synuclein consists of a 140 amino acid polypeptide. The wild type sequence of human α-synuclein can be found in FIG. 20 (SEQ ID NO:49). α-Synuclein normally exists as an soluble monomeric protein but can adopt several different folded confirmations depending on its environment. Monomeric α-synuclein can also aggregate into oligomers and into higher molecular weight insoluble fibrils.
Diseases associated with abnormalities in synucleins are often referred to as the synucleinopathies. Synucleinopathies include the neurodegenerative conditions, Parkinson's disease (PD), dementia with Lewy bodies (DLB) and multiple system atrophy (MSA). In synucleinopathies it has been shown that soluble α-synuclein oligomers in brain homogenates of PD and DLB are elevated compared to normal brains. In addition the neuropathologic lesions (Lewy bodies) that often characterise the end stage of PD and DLB have largely been found to be composed of fibrillar α-synuclein deposits.
Commercially available α-synuclein antibodies are known, and are widely used for characterising PD pathology in the brain. However such antibodies are non-specific and recognise both the monomeric and the aggregated forms of α-synuclein, and may not recognise all aggregated forms of α-synuclein.
Known α-synuclein antibodies include Syn-1 (BD Biosciences) and mAb 211 (Santa Cruz Biotechnology), which are known to bind equally to monomeric and aggregated forms of α-synuclein.
WO2011/104696 discloses antibodies that specifically recognise the protofibril forms of α-synuclein. These antibodies exhibit low binding affinity to α-synuclein fibrils and monomers.